Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, 77807, USA.
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Sci Rep. 2020 Jul 23;10(1):12320. doi: 10.1038/s41598-020-69196-4.
The intrinsic lymphatic contractile activity is necessary for proper lymph transport. Mesenteric lymphatic vessels from high-fructose diet-induced metabolic syndrome (MetSyn) rats exhibited impairments in its intrinsic phasic contractile activity; however, the molecular mechanisms responsible for the weaker lymphatic pumping activity in MetSyn conditions are unknown. Several metabolic disease models have shown that dysregulation of sarcoplasmic reticulum Ca ATPase (SERCA) pump is one of the key determinants of the phenotypes seen in various muscle tissues. Hence, we hypothesized that a decrease in SERCA pump expression and/or activity in lymphatic muscle influences the diminished lymphatic vessel contractions in MetSyn animals. Results demonstrated that SERCA inhibitor, thapsigargin, significantly reduced lymphatic phasic contractile frequency and amplitude in control vessels, whereas, the reduced MetSyn lymphatic contractile activity was not further diminished by thapsigargin. While SERCA2a expression was significantly decreased in MetSyn lymphatic vessels, myosin light chain 20, MLC phosphorylation was increased in these vessels. Additionally, insulin resistant lymphatic muscle cells exhibited elevated intracellular calcium and decreased SERCA2a expression and activity. The SERCA activator, CDN 1163 partially restored lymphatic contractile activity in MetSyn lymphatic vessel by increasing phasic contractile frequency. Thus, our data provide the first evidence that SERCA2a modulates the lymphatic pumping activity by regulating phasic contractile amplitude and frequency, but not the lymphatic tone. Diminished lymphatic contractile activity in the vessels from the MetSyn animal is associated with the decreased SERCA2a expression and impaired SERCA2 activity in lymphatic muscle.
内在的淋巴管收缩活动对于正常的淋巴转运是必要的。高果糖饮食诱导的代谢综合征（MetSyn）大鼠的肠系膜淋巴管内在的时相性收缩活动受损；然而，导致 MetSyn 条件下较弱的淋巴管泵送活性的分子机制尚不清楚。几个代谢疾病模型表明，肌浆网 Ca2+-ATP 酶（SERCA）泵的失调是各种肌肉组织中所见表型的关键决定因素之一。因此，我们假设淋巴管肌中 SERCA 泵表达和/或活性的降低会影响 MetSyn 动物中淋巴管收缩的减弱。结果表明，SERCA 抑制剂 thapsigargin 显著降低了对照淋巴管的时相性收缩频率和幅度，而 MetSyn 淋巴管的收缩活性降低并没有进一步被 thapsigargin 降低。虽然 MetSyn 淋巴管中 SERCA2a 的表达显著降低，但这些血管中的肌球蛋白轻链 20 和 MLC 磷酸化增加。此外，胰岛素抵抗的淋巴管肌细胞表现出细胞内钙升高和 SERCA2a 表达和活性降低。SERCA 激活剂 CDN 1163 通过增加时相性收缩频率部分恢复了 MetSyn 淋巴管的淋巴收缩活性。因此，我们的数据首次提供了证据表明，SERCA2a 通过调节时相性收缩幅度和频率来调节淋巴管的泵送活性，但不调节淋巴管张力。MetSyn 动物血管中淋巴管收缩活性的降低与淋巴管肌中 SERCA2a 表达的减少和 SERCA2 活性的受损有关。
